Computational analysis to identify key factors governing drug encapsulation of cyclodextrin-based metal-organic frameworks.

Metal-organic frameworks (MOFs) are porous materials formed by metal ions and organic ligands. MOFs are promising candidates for Drug Delivery Systems (DDS) because of their high porosity and tunable pore properties. Cyclodextrin-based MOFs (CD-MOFs) have gained attention as biocompatible MOFs for drug-delivery applications. This study investigates the encapsulation behavior of drug molecules in γ-CD-MOFs through computational simulations. The chemical potential of 5-fluorouracil (5FU) was calculated as - 40.13 kJ/mol using the Widom insertion method within the canonical Monte Carlo (CMC) simulation. The predicted drug-loaded amount was 128.84 mg-drug/g-MOF, which closely matched the experimental value of 143.0 mg-drug/g-MOF. Grand canonical Monte Carlo (GCMC) simulations of 26 types of drugs showed that drugs with molecular weights of approximately 300 exhibited the highest loading, primarily in hydrophobic pores. Multiple regression analysis was performed for the total and hydrophobic drug loaded amounts with 17 independent variables, including molecular weight, bounding box dimensions, and functional groups. The results revealed that halogen atoms and benzene rings positively influenced encapsulation efficiency, whereas hydrophobic functional groups enhanced drug loading in hydrophobic pores. Additionally, larger molecular sizes cause steric hindrance, thereby decreasing drug loading. These findings provide valuable insights for the optimization of MOF-based drug delivery systems.